A novel microdeletion syndrome at 3q13.31 characterised by developmental delay, postnatal overgrowth, hypoplastic male genitals, and characteristic facial features.

BACKGROUND: Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype-phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. METHODS: Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. RESULTS: The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype-phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. CONCLUSION: A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.

Interstitial Deletions at 6q14.1-q15 Associated with Obesity, Developmental Delay and a Distinct Clinical Phenotype.

BACKGROUND: Interstitial deletions of the long arm of chromosome 6 have been described in several patients with obesity and a Prader-Willi-like phenotype. Haploinsufficiency of the SIM1 gene located at 6q16.3 is suggested as being responsible for the regulation of body weight. Here we report on 2 patients with interstitial deletions at 6q14.1-q15 presenting with obesity and symptoms strikingly similar to those reported for deletions involving the SIM1 gene despite not having a deletion of this gene. METHODS: Array comparative genomic hybridisation was used to diagnose 2 children with obesity and developmental delay, revealing 2 interstitial deletions at 6q14.1-q15 of 8.73 and 4.50 Mb, respectively, and a region of overlap of 4.2-Mb. RESULTS: The similar phenotype in the 2 patients was most likely due to a 4.2-Mb common microdeletion at 6q14.1-q15. Another patient has previously been described with an overlapping deletion. The 3 patients share several features, such as developmental delay, obesity, hernia, rounded face with full cheeks, epicanthal folds, short palpebral fissures, bulbous nose, large ears, and syndactyly between toes II and III. CONCLUSIONS: Together with a previously reported patient, our study suggests that the detected deletions may represent a novel clinically recognisable microdeletion syndrome caused by haploinsufficiency of dosage-sensitive genes in the 6q14.1-q15 region.

Late effects of early growth hormone treatment in Down syndrome.

OBJECTIVE: Down syndrome (DS) is associated with short stature and psychomotor delay. We have previously shown that growth hormone (GH) treatment during infancy and childhood normalizes growth velocity and improves fine motor skill performance in DS. The aim of this study was to investigate late effects of early GH treatment on growth and psychomotor development in the DS subjects from the previous trial. DESIGN: Twelve of 15 adolescents with DS (3 F) from the GH group and 10 of 15 controls (5 F) participated in this follow-up study. Fifteen other subjects with DS (6 F) were included as controls in anthropometric analyses. Cognitive function was assessed with the Leiter International Performance Scale-Revised (Leiter-R) and selected subtests of the Wechsler Intelligence Scale for Children, Third edition (WISC-III). The Bruininks-Oseretsky Test of Motor Proficiency, Second edition (BOT-2), was used to assess general motor ability. RESULTS: Although early GH treatment had no effect on final height, the treated subjects had a greater head circumference standard deviation score (SDS) than the controls (-1.6 SDS vs. -2.2 SDS). The adolescents previously treated with GH had scores above those of the controls in all subtests of Leiter-R and WISC-III, but no difference in Brief IQ-score was seen between the groups. The age-adjusted motor performance of all subjects was below -2 SD, but the GH-treated subjects performed better than the controls in all but one subtest. CONCLUSION: The combined finding of a greater head circumference SDS and better psychomotor performance indicates that DS subjects may benefit from early GH treatment.

Normal growth hormone secretion in overweight young adults with Down syndrome.

Down syndrome (DS) is associated with short stature and obesity. Adults with DS have several features in common with growth hormone (GH) deficient adult subjects. The aim of this study was to investigate GH secretion in young adults with DS and its relation to body composition as well as glucose and lipid metabolism. Ten young adults with DS (aged 24-32 years; 5 F) and ten controls matched for age and sex were examined regarding spontaneous nocturnal GH secretion and body composition. Stable isotope tracers were used to study glucose and lipid metabolism in the DS subjects. There was no difference in secretion of GH between the DS subjects and controls. The DS subjects had a higher BMI, fat mass proportion and HOMA (homeostasis model assessment) index compared with the controls. The rates of production of glucose and glycerol (reflecting lipolysis) in the DS subjects were increased (15.5+/-5.07 and 3.5+/-1.68 micromol/kg/min, respectively). The DS subjects showed normal GH secretion despite increased BMI and fat mass. The increased HOMA index and high rate of glucose production indicate peripheral and hepatic insulin resistance in adult DS subjects.

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1.

Noonan syndrome (NS) and neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, whereas skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 -a condition known as neurofibromatosis-Noonan syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.

Increased neonatal thyrotropin in Down syndrome.

AIM: Down syndrome (DS) is frequently associated with thyroid dysfunction. The aim of this study was to investigate the blood concentration of thyrotropin (TSH) observed at neonatal screening of infants with DS and its possible association with development of hypothyroidism during childhood. METHODS: TSH levels from neonatal screening of 73 children (34 F) with DS born in 1986-1996 were studied retrospectively and compared with those of controls. The DS children were followed up regarding thyroid function to the age of 10 years in this descriptive study. RESULTS: The DS infants had a higher mean TSH level and a higher TSH standard deviation score (SDS) than controls (7.0 +/- 7.45 mU/L vs. 3.9 +/- 2.43 mU/L and 1.1 +/- 2.67 vs. 0, respectively). The differences were mainly attributable to higher values in the male DS children. The TSH level at screening did not predict thyroid dysfunction during childhood. CONCLUSION: Infants with DS, especially boys, showed elevated levels of TSH at neonatal screening, indicating the occurrence of mild hypothyroidism already in early life. The TSH levels could not predict development of manifest thyroid disease later in childhood.

Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders.

BACKGROUND: Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFC) are related disorders associated with disrupted RAS/RAF/MEK/ERK signalling. NS, characterised by facial dysmorphism, congenital heart defects and short stature, is caused by mutations in the genes PTPN11, SOS1, KRAS and RAF1. CFC is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2. METHODS: A comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated patients without mutations in PTPN11 is presented. RESULTS: Mutations were identified in seven patients with CFC (two in BRAF, one in KRAS, one in MEK1, two in MEK2 and one in SOS1). Two mutations were novel: MEK1 E203Q and MEK2 F57L. The SOS1 E433K mutation, identified in a patient diagnosed with CFC, has previously been reported in patients with NS. In one patient with NS, we also identified a mutation, BRAF K499E, that has previously been reported in patients with CFC. We thus suggest involvement of BRAF in the pathogenesis of NS also. CONCLUSIONS: Taken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even represent allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, for example, NS-PTPN11-associated or CFC-BRAF-associated syndromes after the genetic defect has been established, as this may affect the prognosis and treatment of the patients.

Whole-genome array-CGH for detection of submicroscopic chromosomal imbalances in children with mental retardation.

Chromosomal imbalances are the major cause of mental retardation (MR). Many of these imbalances are caused by submicroscopic deletions or duplications not detected by conventional cytogenetic methods. Microarray-based comparative genomic hybridization (array-CGH) is considered to be superior for the investigation of chromosomal aberrations in children with MR, and has been demonstrated to improve the diagnostic detection rate of these small chromosomal abnormalities. In this study we used 1 Mb genome-wide array-CGH to screen 48 children with MR and congenital malformations for submicroscopic chromosomal imbalances, where the underlying cause was unknown. All children were clinically investigated and subtelomere FISH analysis had been performed in all cases. Suspected microdeletion syndromes such as deletion 22q11.2, Williams-Beuren and Angelman syndromes were excluded before array-CGH analysis was performed. We identified de novo interstitial chromosomal imbalances in two patients (4%), and an interstitial deletion inherited from an affected mother in one patient (2%). In another two of the children (4%), suspected imbalances were detected but were also found in one of the non-affected parents. The yield of identified de novo alterations detected in this study is somewhat less than previously described, and might reflect the importance of which selection criterion of patients to be used before array-CGH analysis is performed. However, array-CGH proved to be a high-quality and reliable tool for genome-wide screening of MR patients of unknown etiology.

Sickness absence in Swedish parents of children with Down's syndrome: relation to self-perceived health, stress and sense of coherence.

BACKGROUND: The aims of present study were to study sickness absence among Swedish parents of children with Down's syndrome (DS) and to compare their rates of absence with those of control parents. Sickness absence data for 165 DS parents were compared with those for 174 control parents; all data were for the period 1997-2000. Sickness absence rates were also related to parental self-perceived health, stress and sense of coherence. METHODS: The self-administrated measures of parental self-perceived health, stress and sense of coherence were compared with the number of days of sickness absence. RESULTS: In about two-thirds of the parents in both the study and the control group, no days of sickness absence were registered. Six of the DS parents had remarkably large numbers of days of sickness absence (more than 100 per year). None of the control parents had such high sickness absence rates. It is speculated that there is a small group (less than 5%) of parents who are more vulnerable to the birth of a child with DS. Apart from these six DS parents, sickness absence was not more frequent among the DS parents than among the control parents. DS parents stayed at home to care for their sick DS child three times more often than control parents did for their non-disabled child. DS fathers took greater responsibility in the care of their temporarily sick child and stayed at home to care for the child even more often than control mothers did. DS parents with sickness periods experienced small deterioration in self-perceived health, significantly higher stress and decreased sense of coherence in comparison with parents without sickness periods. CONCLUSIONS: There was a great similarity in sick leave rates due to one's own sickness between DS and control parents, but a small group of DS parents (<5%) may be more vulnerable. DS fathers stayed at home to care for their sick DS child remarkably often.

Maternal and neonatal factors and mortality in children with Down syndrome born in 1973-1980 and 1995-1998.

AIMS: To investigate maternal and neonatal factors in Down syndrome (DS) at birth, the impact of a congenital heart defect (CHD) on these factors and changes over time. METHODS: Medical data of children with DS born in northern Sweden in the periods 1973-1980 (n = 219) and 1995-1998 (n = 88) obtained from the Swedish Medical Birth Register were compared. A comparison with the general population on a group level was also made. RESULTS: The main finding was a reduction in infant mortality in DS, from 14.2% to 2.3% in 1995-1998 (p < 0.001), but this was still significantly higher than in the general population. The rate of Caesarean sections increased over time (from 14.5% to 27.3%, p < 0.05) even after adjustment for increased maternal age. No change over time was detected in the following rates: premature birth (gestational age < or = 36) (25%); asphyxia (5-min Apgar score < or = 6) (8%); low birthweight (< 2500 g) (14%); or small for gestational age (SGA) (14%); all rates were significantly higher than those of the general population. A CHD did not seem to influence the rates of these factors in a logistic regression model. CONCLUSION: Infant mortality decreased substantially over time in the DS group, whereas there was no reduction in the rate of asphyxia, SGA, low birthweight or prematurity. The presence of a CHD did not influence any of the neonatal factors studied.

A novel nonsense mutation of the mineralocorticoid receptor gene in a Swedish family with pseudohypoaldosteronism type I (PHA1).

Pseudohypoaldosteronism type I (PHA1) is a condition associated with salt wasting leading to dehydration, hypotension, hyperkalemia, and metabolic acidosis. Sporadic cases and two familial forms, one autosomal dominant and one autosomal recessive form, have been described. The autosomal dominant or sporadic form manifests milder salt wasting that remits with age. Mutations in the gene encoding the mineralocorticoid receptor (MR) have been identified in patients with the autosomal dominant inheritance. However, recent studies suggest that the autosomal dominant and sporadic forms are genetically heterogeneous and that additional genes might be involved. We report on the study of 15 members of a Swedish five-generation family with the autosomal dominant form of PHA1. Interestingly, neuropathy was found in two of five affected individuals. A novel heterozygous nonsense mutation C436X in exon 2 was identified in the index patient by linkage analysis, PCR, and direct sequencing of the MR gene. Analysis of the family demonstrated that the mutation segregated with PHA1 in the family. It is unclear whether the neuropathy is associated with the mutation found. Our results together with previously published data suggest that loss-of-function mutations of the MR gene located at 4q31.1, commonly are associated with the autosomal dominant form of PHA1.

Swedish parents of children with Down's syndrome.

Becoming parents of a child with Down's syndrome (DS) challenges the adjustment ability in parenthood. Individuals with higher sense of coherence (SOC) are supposed to manage stressors better than those with lower SOC. The aims of this study were to investigate parental self-perceived stress, SOC, frequency of gainful employment and amount of time spent on child care in Swedish DS parents (165 parents; 86 mothers, 79 fathers) and to compare those with control parents of healthy children (169 parents; 87 mothers, 82 fathers). The mean age of the children was 4.7 years. Parents responded to questionnaires separately including Hymovich's Parent Perception Inventory as stress measurement and Antonovsky's short version of the Orientation to Life. No differences concerning total employment rate were observed, but the DS mothers were more often employed part-time than control mothers. The DS parents did not spend more time on child care than the control parents and they did not differ in mean SOC score, but the DS parents perceived greater stress. The differences in stress, particularly between the DS and control mothers, were related to time-demanding areas. Parents with high SOC scores experienced significantly less self-perceived stress.

Chondrodysplasia punctata (CDP) with features of the tibia-metacarpal type and maternal phenytoin treatment during pregnancy.

We describe a 2-year-old boy with chondrodysplasia punctata (CDP). The boy was exposed to phenytoin, in combination with carbamazepine, during pregnancy. There has been previous evidence for a connection between phenytoin exposure during pregnancy and chondrodysplasia punctata. The boy had clinical and some radiological characteristic features of CDP, of the tibia-metacarpal type. We know of no other report on a child exposed to phenytoin during pregnancy who developed CDP of this type.

Growth charts for Down's syndrome from birth to 18 years of age.

BACKGROUND: Growth in children with Down's syndrome (DS) differs markedly from that of normal children. The use of DS specific growth charts is important for diagnosis of associated diseases, such as coeliac disease and hypothyroidism, which may further impair growth. AIMS: To present Swedish DS specific growth charts. METHODS: The growth charts are based on a combination of longitudinal and cross sectional data from 4832 examinations of 354 individuals with DS (203 males, 151 females), born in 1970-97. RESULTS: Mean birth length was 48 cm in both sexes. Final height, 161.5 cm for males and 147.5 cm for females, was reached at relatively young ages, 16 and 15 years, respectively. Mean birth weight was 3.0 kg for boys and 2.9 kg for girls. A body mass index (BMI) >25 kg/m(2) at 18 years of age was observed in 31% of the males and 36% of the females. Head growth was impaired, resulting in a SDS for head circumference of -0.5 (Swedish standard) at birth decreasing to -2.0 at 4 years of age. CONCLUSION: Despite growth retardation the difference in height between the sexes is the same as that found in healthy individuals. Even though puberty appears somewhat early, the charts show that DS individuals have a decreased pubertal growth rate. Our growth charts show that European boys with DS are taller than corresponding American boys, whereas European girls with DS, although being lighter, have similar height to corresponding American girls.

Utilization of medical care among children with Down's syndrome.

BACKGROUND: The present authors have previously found an increased mortality rate in children with Down's syndrome (DS) and a congenital heart defect (CHD). The aim of the present study was to investigate the utilization of medical care in relation to congenital malformations in DS. METHOD: Retrospectively, 211 children with DS born between 1973 and 1980 in the northern part of Sweden were followed up for at least 17 years (1973-1997). The duration of neonatal care was compared with that of children with DS born between 1995 and 1998 in the same region. RESULTS: Neonatal care was reduced over time. Almost 50% of the children had CHD, and before 10 years of age, these subjects were admitted for inpatient care twice as often as children with DS who did not have malformations, and had more than 12 times as many inpatient days per month. The existence of a gastrointestinal or other malformation increased inpatient days per month four and two times, respectively, compared to healthy children with DS. During the first 10 years of life, children with DS and a CHD accounted for 71% of all inpatient days caused by infections. No gender differences were observed. CONCLUSIONS: At a group level, the presence of a CHD was the most important congenital abnormality in determining utilization of medical care and the burden of infections in the population of children with DS.

First information and support provided to parents of children with Down syndrome in Sweden: clinical goals and parental experiences.

UNLABELLED: When parents are informed that their newborn child has Down syndrome (DS), they often respond with a traumatic crisis reaction. The aims of this study were to assess the clinical goals regarding the first information and support provided to parents of newborn children with DS at the Swedish paediatric departments, and to analyse the parents' experiences of how they were first informed and treated. Data were collected during 1992-1993 from all of the 51 departments of paediatrics in Sweden. Information on the parents' experiences, collected retrospectively in 1996, was based on recollection by 165 parents of 86 children with DS born between 1989 and 1993 at 10 of the paediatric departments considered representative for Sweden. Seventy-five percent of the families were informed about the diagnosis within 24 h post partum. Some parents felt they were informed too late, and a few parents that they were told too soon. Half of the parents were satisfied with the timing. About 70% of the parents considered the information insufficient and 60% felt that they had been unsupported. Seventy percent would have liked more frequent information. Parental criticisms concerning the way in which the information was provided were that they received too much negative information about DS and that both the communication skills and the basic knowledge of DS on the part of the professionals could have been better. CONCLUSION: The Swedish paediatric departments fall short of their reported strong clinical goals regarding the initial information in Sweden, and improvements in this area are desirable.

A balanced reciprocal translocation t(5;7)(q14;q32) associated with autistic disorder: molecular analysis of the chromosome 7 breakpoint.

Autism is a neuropsychiatric disorder characterized by impairments in social interaction, restricted and stereotypic pattern of interest with onset by 3 years of age. The results of genetic linkage studied for autistic disorder (AD) have suggested a susceptibility locus for the disease on the long arm of chromosome 7. We report a girl with AD and a balanced reciprocal translocation t(5;7)(q14;q32). The mother carries the translocation but do not express the disease. Fluorescent in situ hybridization (FISH) analysis with chromosome 7-specific YAC clones showed that the breakpoint coincides with the candidate region for AD. We identified a PAC clone that spans the translocation breakpoint and the breakpoint was mapped to a 2 kb region. Mutation screening of the genes SSBP and T2R3 located just centromeric to the breakpoint was performed in a set of 29 unrelated autistic sibling pairs who shared at least one chromosome 7 haplotype. We found no sequence variations, which predict amino acid alterations. Two single nucleotide polymorphisms were identified in the T2R3 gene, and associations between allele variants and AD in our population were not found. The methylation pattern of different chromosome 7 regions in the patient's genomic DNA appears normal. Here we report the clinical presentation of the patient with AD and the characterization of the genomic organization across the breakpoint at 7q32. The precise localization of the breakpoint on 7q32 may be relevant for further linkage studies and molecular analysis of AD in this region.

Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses.

OBJECTIVE: To investigate whether the rate of caffeine metabolism influences spontaneous abortion risk. METHODS: We studied 101 women with normal karyotype spontaneous abortions and 953 pregnant women at 6-12 gestational weeks. Participants reported on caffeine intake and provided urine for phenotyping cytochrome P4501A2 (CYP1A2) activity and blood for genotyping N-acetylation (NAT2) status. We calculated odds ratios (OR) and 95% confidence intervals (CI) to evaluate the association between each of the two metabolic indices and spontaneous abortion risk and also the potential interaction between caffeine intake and metabolic activity on such risk. In calculating the associations between the metabolic indices and risk of spontaneous abortion, we had 80% power to detect an OR of 2.1, with a Type I error of 0.05. RESULTS: Slow acetylators had a nonsignificantly increased risk for spontaneous abortion (OR 1.36, 95% CI 0.84, 2.21) and recurrent spontaneous abortion (OR 2.51, 95% CI 0.81, 7.76). In contrast, low CYP1A2 activity was associated with a significantly decreased risk for spontaneous abortion (OR 0.35, 95% CI 0.20, 0.63). Caffeine was a risk factor for spontaneous abortion among women with high, but not low, CYP1A2 activity (OR 2.42, 95% CI 1.01, 5.80 for 100-299 mg/day; OR 3.17, 95% CI 1.22, 8.22 for 300 mg/day or more, among women with high CYP1A2 activity). CONCLUSION: The findings indicate that high CYP1A2 activity may increase the risk of spontaneous abortion, independently or by modifying the effect of caffeine. The results regarding NAT2 are less conclusive but suggest that slow acetylators may be at elevated risk of spontaneous abortion.

Self-perceived health in Swedish parents of children with Down's syndrome.

In this comparative study, self-perceived health was investigated in 165 parents of 86 children with Down's syndrome (DS), using the Swedish version of the SF-36 questionnaire. Questionnaires were mailed to parents of children with DS in a defined Swedish population. The results were compared with those in a randomised control group of parents from the Swedish SF-36 norm population. Mothers and fathers replied separately. Student's t-test with the Bonferroni correction was used for multiple statistical comparisons. The mothers of children with DS ('DS mothers') had significantly lower, less favourable scores than did the fathers of DS children ('DS fathers') in the Vitality (p < 0.0005) domain. Further, DS mothers spent significantly more time in caring for their child with DS than did the DS fathers (p < 0.0001). DS mothers also had lower scores than the mothers of the control group in the Vitality (p < 0.001) and Mental Health (p < 0.001) domains. DS fathers and control fathers differed significantly in the Mental Health domain (p < 0.002), but not otherwise. In conclusion, DS mothers showed poorer health than their spouses and the control mothers. No differences similar to those found between the DS mothers and DS fathers were observed between control mothers and control fathers.